P53 Dysfunction in Neurodegenerative Diseases - The Cause or Effect of Pathological Changes?

Abstract

Neurodegenerative diseases are a heterogeneous, mostly age-associated group of disorders characterized by progressive neuronal loss, the most prevalent being Alzheimer disease. It is anticipated that, with continuously increasing life expectancy, these diseases will pose a serious social and health problem in the near feature. Meanwhile, however, their etiology remains largely obscure even though all possible novel clues are being thoroughly examined. In this regard, a concept has been proposed that p53, as a transcription factor controlling many vital cellular pathways including apoptosis, may contribute to neuronal death common to all neurodegenerative disorders. In this work, we review the research devoted to the possible role of p53 in the pathogenesis of these diseases. We not only describe aberrant changes in p53 level/activity observed in CNS regions affected by particular diseases but, most importantly, put special attention to the complicated reciprocal regulatory ties existing between p53 and proteins commonly regarded as pathological hallmarks of these diseases, with the ultimate goal to identify the primary element of their pathogenesis.

Keywords: Alzheimer disease; Parkinson disease; apoptosis; neurodegenerative diseases; neuronal loss; p53.

Figure 1.. Simplified scheme of p53 involvement in neurodegenerative diseases

p53 level and activity in neurons can increase not only as a result of oxidative stress and DNA damage but also due to aberrant regulation of its expression by mutated or erroneously cleaved proteins involved in neurodegeneration. Increased expression and activation of p53 entails enhanced expression of genes responsible for apoptosis or/and cell cycle arrest and, in consequence, may trigger neuronal death.